The present invention is of a dispersible concentrate preparation for the delivery of cyclosporin, and in particular, of a dispersible concentrate preparation which provides a delivery system with high bioavailability of cyclosporin and related substances.
Many dispersion systems are currently in use as, or being explored for use as, carriers of substances, particularly biologically active compounds. These systems are designed to protect the substance from the environment during delivery and to provide a controlled release of the substance to a targeted area. In some cases, the goal is to target specific sites in the body using the dispersion. In other cases, the goal is to prepare a drug carrier system that acts as a reservoir at the site of injection.
Dispersion systems used for pharmaceutical and cosmetic formulations can be categorized as either suspensions or emulsions. Suspensions are defined as solid particles ranging in size from a few nanometers up to hundreds of microns, dispersed in an aqueous or nonaqueous medium using suspending agents. Solid particles include microspheres, microcapsules, and nanospheres.
Emulsions can be defined as dispersions of one liquid in another, stabilized by an interfacial film of emulsifiers such as surfactants and lipids. Despite their long history, emulsions are used less often today than many other dosage forms due to the inherent instability. Emulsion formulations include water in oil and oil in water emulsions, multiple water/oil/water emulsions, microemulsions, microdroplets, and liposomes.
A microemulsion is a transparent or substantially transparent emulsion which is formed spontaneously or substantially spontaneously when its components are brought into contact. Microemulsions are thermodynamically stable and contain dispersed particles or droplets of a size less than about 200 nm. Generally microemulsions feature droplets or particles having a mean diameter of less than about 150 nm. These particles may be spherical, although other structures are feasible, such as liquid crystals with lamellar, hexagonal or isotropic symmetries. Microemulsions are usually stable over periods in excess of 24 hours.
Microemulsions can also be used as a “microemulsion preconcentrate”, defined herein as a composition which spontaneously forms a microemulsion in an aqueous medium, for example in water, upon dilution, or in the gastric juices after oral application. Dilution of the microemulsion in water can be for example from about 1:1 fold to about 1:10 fold dilution.
As noted above, while emulsion based delivery systems are useful for certain applications, the delivering vesicles are subject to physical rupture because of the delicate nature of the liquid/membrane/liquid structure. Emulsion based delivery systems also have relatively short release times. Further, it is difficult to isolate emulsion based vesicles from the aqueous media used for storage for subsequent reconstitution.
In spite of these difficulties, microemulsions have been the only successful delivery systems for certain types of pharmaceutical compounds, particularly compounds such as members of the cyclosporin class, which are cyclic oligopeptides. The cyclosporin class includes substances having pharmaceutical utility, for example as immunosuppressive agents, anti-parasitic agents and agents for the reversal of multi-drug resistance, as known and described in the art. Examples of such cyclosporins include, but are not limited to, Cyclosporin A (also known as and referred to herein as “Ciclosporin”), Cyclosporin G, [0-(2-hydroxyethyl)-(D)Ser]2-Ciclosporin and [3′-deshydroxy-3′-ket-MeBmt]1-[Val)]2-Ciclosporin.
The first of the cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin (Cyclosporine). Ciclosporin is the cyclosporin of formula (I): wherein —MeBmt— represents the N-methyl-(4R)-4-but-2E-en-1-yl-4-methyl-(L)threonyl residue of formula (II): in which —x-y— is —CH═CH— (trans). Ciclosporin is well known as an immunosupressive agent. In addition, Ciclosporin is being examined for the treatment of autoimmune and inflammatory diseases.
Since the original discovery of Ciclosporin, a wide variety of naturally occurring cyclosporins have been isolated and identified, and many further non-natural cyclosporins have been prepared by total- or semi-synthetic means or by the application of modified culture techniques. The class comprised by the cyclosporins now includes, for example, the naturally occurring cyclosporins A through Z [c.f. Traber et al., Helv. Chim. Acta. 60: 1247-1255, 1977; Traber et al.. Helv. Chim. Acta. 65: 1655-1667, 1982; Kobel el al., Europ. J. App. Microbio. and Biotech., 14: 273-240 (1982); and von Wartburg el al., Progress in Allergy, 38: 28-45 (1986)], as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins including: the so-called dihydro-cyclosporins, in which the moiety —x-y— of the —MeBmt— residue in Formula (II) above is saturated to give —x-y— of —CH2—CH2—; derivatized cyclosporins (e.g. in which a further substituent is introduced at the α-carbon atom of the sarcosyl residue at the 3-position of the cyclosporin molecule); cyclosporins in which the —MeBmt— residue is present in isomeric form (e.g. in which the configuration across positions 6′ and 7′ of the —MeBmt— residue is cis rather than trans); and cyclosporins in which variant amino acids are incorporated at specific positions within the peptide sequence. Many of these members of the cyclosporin class exhibit pharmaceutical utility which may be comparable to that of Ciclosporin.
Unfortunately, many difficulties have been encountered in the effective administration of Ciclosporin, difficulties which appear to be inherent in the nature of the members of the cyclosporin class. Cyclosporins are characteristically highly hydrophobic, and thus require a lipophilic carrier. The selection of a suitable carrier is particularly critical for the administration of cyclosporins, as the bioavailability of these compounds is known in the art to be highly variable, depending upon the properties of the carrier. Furthermore, these compounds are known to have bioavailability which may vary significantly between individuals. Such variation is particularly dangerous given the side effects of cyclosporins, such as nephrotoxicity. Thus, the suitable carrier must provide good bioavailability of cyclosporins which is substantially consistent between individuals.
As noted previously, cyclosporins may be administered with a microemulsion carrier. This carrier generally contains a hydrophilic solvent, such as liquid PEG200-600, ethylene or propylene glycol, ethanol or propanol, glycerin, water soluble fatty acid C6-C18 esters of sucrose, dimethylisosorbide, ethyl-acetate, glycofurol (fatty acid derivative of a cyclic polyol), PEG derivatives of tocopherol, or PEG-fatty acid esters; a surfactant, such as Tween 20, various PEG (polyethylene glycol) derivatives or phospholipids; a water insoluble oil such as corn oil and other oils from plants and mixtures of oils; and Cremophor™ and similar PEG derivatives of castor oil or other fats which are used as an amphiphilic solvent, emulsifier, surfactant and so forth. Unfortunately, none of these background art formulations provides high bioavailability for cyclosporin.
The currently commercially available formulation is disclosed in U.S. Pat. No. 5,342,625 to Sandoz A.G. This formulation includes a hydrophilic phase, a lipophilic phase and a surfactant. The hydrophilic phase could be a C1-5 alkyl di-or partial-ether of a mono- or poly-oxy-C1-12alkanediol, for example.
PCT Application No. WO 96/13273 to Sandoz describes compositions for cyclosporin and other macrolide drugs such as Rapamycin, containing a hydrophilic phase which includes dimethylisosorbide and/or a lower alkyl alkanoic ester, a lipophilic phase and a surfactant. The particle size after dispersion can be 200 nm but is preferably 100 nm or less. The hydrophilic phase is PEG, propylene glycol and glycofurol or dimethylisosorbide (a bicyclic ether). The bioavailability of a composition containing cyclosporin and the carrier is not disclosed.
PCT Application No. WO 97/19692, also to Sandoz, describes compositions which are based on PEG-derivatives of saturated hydroxy fatty acids such as PEG-hydroxystearate and a low alcohol such as ethanol or propylene glycol. Again, the bioavailability of such a composition is not disclosed.
PCT Application No. WO 98/33512 to Novartis describes compositions for oral administration of cyclosporin which do not contain oil. Instead, these compositions contain a surfactant with HLB 10 or higher and a hydrophilic phase which is polyethylene glycol and/or a lower alcohol (not more than 12%). The formulations are preconcentrates which provide a particle size of 10 to 150 nm upon dispersion. The disclosed advantage of these compositions is their ability to be stably contained within a hard capsule. However, no specific data is disclosed related to the bioavailability of cyclosporin with this composition. As noted above, the bioavailability of cyclosporin is known to be highly variable, depending upon the carrier.
PCT Application No. WO 97/04795 to POLI Industria describes compositions that must contain one polymer, linear or crosslinked PEG and poly (acrylic) or mixtures thereof and monoesters of fatty acids with a short alcohol. Again, the bioavailability of such a composition is not disclosed.
U.S. Pat. No. 5,756,450 to Novartis describes solid formulations for cyclosporin composed of a water soluble monoester of a fatty acid C6-C18 with a polyol, for example a saccharide such as Saccharose monolaurate or raffinose monolaurate. This solvent can be used in combination with other water soluble solvents including PEG, ethanol, ethylene glycol and glycerin. The examples describe solid solutions (powder) of Cyclosporin in saccharose monooleate which is completely soluble in water. Again, the bioavailability of such a composition is not disclosed.
U.S. Pat. Nos. 5,603,951 and 5,639,474 to Hanmi Pham. describe compositions of dimethylisosorbide as a cosurfactant and a primary alcohol, medium chain triglycerides and a surfactant having a HLB value of 10 to 17 such as Tween 20, formulated in soft gelatin capsule. The particle size is about 100 nm. Again, the bioavailability of such a composition is not disclosed.
U.S. Pat. No. 5,583,105 to Biogel describes cyclosporin formulations composed of PEG esters of tocopherol and a lipophilic solvent, an amphiphilic solvent and ethanol. Again, the bioavailability of such a composition is not disclosed.
U.S. Pat. No. 5,614,491 to Dr. Rentschler GmbH, describes formulations of PEG fatty acid monoesters as emulsifying agent and a polyol as solvent. U.S. Pat. No. 5,798,333 to Sherman describes formulations composed of Tocophersolan and a polyhydric alcohol. Tocophersolan is a water soluble surfactant which dissolves cyclosporin only at a 7:1 ratio.
U.S. Pat. No. 5,827,822 to Sangstat describes formulations of alcohol and a PEG surfactant forming particle size between 200 and 400 nm.
European Patent Application No. EP 0760237 A1 to Cipla describes a composition containing: vegetable oil triglycerides (castor, peanut, or coconut oil), phospholipid, a surfactant (Tween 20, polyoxyl-40-hydrogenated castor oil), and a hydrophilic solvent, propylene glycol. Again, the bioavailability of cyclosporin administered with such a composition is not disclosed.
None of these disclosed background art carrier formulations features a hydrophilic solvent which is a lower alkyl ester of hydroxyalkanoic acid, such as ethyl lactate or N-methyl pyrrolidone. Moreover, none of these disclosed background art carrier formulations features a combination of a surfactant with high HLB and a surfactant with low HLB. Furthermore, none of these background art carrier formulations is disclosed as having high bioavailability. Thus, the background art carrier formulations do not appear to possess the advantageous high bioavailability of the present invention, as described in greater detail below.
There is thus an unmet need for, and it would be useful to have, a composition for the administration of cyclosporins, particularly for oral administration, which would provide a high bioavailability, and which would preferably contain a hydrophilic solvent which is a lower alkyl ester of hydroxyalkanoic acid, and a surfactant which is preferably a combination of a surfactant with high HLB and a surfactant with low HLB.